Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine. The innate immune system enables the host to differentiate self from invading microbes, discriminate among pathogens, and initiate a cascade of inflammation. These functions, which are orchestrated by Toll-like Receptors (TLRs) and Nod-like Receptors (NLRs), regulate bacterial killing and influence formation of the adaptive immune response as well as host survival. Although these gene families are critical mediators of the immune response to pathogens, the influence of common TLR or NLR polymorphisms on susceptibility to infection in humans is poorly understood. Over the past 10 years, my research goals have been to understand the genetic and immunologic factors that influence human susceptibility to infections such as tuberculosis and to use this knowledge to design more effective vaccines and therapies. These projects include human genetic case-control studies which examine whether allelic variants of innate immunity genes are associated with human infections. These association studies are coupled with mechanistic experiments designed to determine which molecular and cellular responses are regulated by these variants. The research aims of this proposal are to understand the clinical significance of variation of macrophage and pulmonary innate immune responses with molecular, cellular, and human genetic models. My mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity. Currently, there are 7 trainees working in my laboratory and each is examining a different aspect of the role of innate immunity polymorphisms in susceptibility to infection. We hypothesize that common variants of innate immunity genes regulate the immune response to pulmonary pathogens. We recently identified several polymorphisms in TOLLIP, a gene which regulates TLR-signaling, that are associated with susceptibility to Mycobacterium tuberculosis (MTb). In Aim 1, we will examine the mechanism of how these TOLLIP polymorphisms regulate cellular function in response to infection with MTb. In Aim 2, we will examine which aspects of the immune response to MTb are regulated by TOLLIP. These research aims will be coordinated with a mentoring aim to develop a centralized innate immunity bioassay bank that can be utilized by all trainees in the laboratory. Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine. The research aims of this proposal are to examine how variation of innate immunity genes regulates the pulmonary immune response to tuberculosis. The mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity.